The pharmacology and molecular pharmacology of various gastrointestinal (GI) peptides are being investigated. Two peptide receptor families investigated during the year are those for bombesin- (Bn) related peptides and for VIP-related peptides. Bn-related peptides (GRP, NMB) interact primarily with three distinct receptors (GRP-R, NMB-R)and the orphan receptor, BRS-3 to mediate a number of effects in the GI tract and central nervous system (CNS). Using information from structure-function studies by us and others we have synthesized high affinity Bn and VIP analogues that were metabolically stable and that be could to cytotoxic agents as well as performed receptor ligand structure function studies to gain insights into the molecular determinants of high affinity receptor interaction. We also studied the signaling cascade for internalization of Bombesin-related peptides because of the importance of this process in mediating cellular uptake that could be used by cytotoxic agents.